Octahydrophenanthrene-2-carboxylic acids and derivatives thereof



Patented Dec. 19, 1950 OCTAHYDROPHENANTHRENE 2 CARBOX- YLIC AQIDS ANDDERIVATIVES THEREOF Karl Miescher, Riehen, Jules Heer, Binningen, andJean-Rene Billeter and Georg Anner, Basel, Switzerland, assignors toCiba Pharmaceutical Products, 1110., Summit,

No Drawing. Application April 1a, 1948, Serial No. 20,824. InSwitzerland January 10, 1944 3 Claims. 1

The present invention relates to a process for the preparation ofoctahydrophenanthrene-2 carboxylic acids and derivatives thereof. It isa continuatin-in-part of our copending application Ser. No. 542,812,filed June 29, 1944, now U. S. Patent No, 2,459,834. The latterdiscloses a process for the preparation of hydrophenan-'threne-2-carboxy1ic acids and derivatives thereof by reacting al-keto-hydrophenanthrene which "contains in the 2-position, in additionto a hydrocarbon radical, a functionally converted carboxyl group, andin the l-position a free phenolic hydroxygroup or a substituentconvertible into a free phenolic hydroxy group, with an organoj metalcompound in order to introduce a hydrocarbon radical into the1-position, eliminating the newly introduced tertiary hydroxyl groupdirectly or indirectly, and, if desired, converting the functionallyconverted carboxyl group in the Z-position into a free carboxyl groupand/ or converting the substituent in the 7-position into a freehydroxyl group and hydrogenating non-aromatic carbon-to-carbon multiplebonds at any desired.

stage after the reaction with the organo-metal compound.

It is possible by theabove process to obtainoctahydrophenanthrene-2-carboxylic acids and derivatives thereof,However, the final products are obtained in the form of complex mixturesfrom which the highly active components can be isolated only withconsiderablelosses, whereby the resultant yields are commensuratelyimpaired.

The present invention is based on the observation that the foregoingdifficulty can be circumvented and the desired final products obtainedin good yield by using the l-keto-octahydrophenanthrenes serving asstarting materials in the form of the individual racemates or opticalantipodes. The starting materials contain three asymmetrical carbonatoms, which correspond to 4 racemates or 8 optically active antipodes.The final products contain a further asymmetrical carbon atom so thatthe number of isomers is increased to 8 racemates or 16 optically activeantipodes.

Accordingly, as compared with the process of the aforesaid application,the present process has the advantage that, instead of a highly complexmixture from which the components are almost in-' separable, there areformed at most 2 racemates when a homogeneous keto-ester racemate isused};

or 2 optically active antipodes when a homo-, geneous optically activeketo-ester is used, which, racemates or antipodes can then be separatedinto.

the pure components without difliculty, for example, by fractionalcrystallization, chromatog raphy or sublimation. By suitably selectingthe reaction conditions the synthesis can be so conducted as to favormore strongly the formation? of one of the two racemates or one of thetwo optical antipodes.

In other. respects the starting materials may contain the samefunctional groups as those ofthe aforesaid application. Thus, they maycon-,1 tain in the l-position a keto-group and in thel ii-position ahydrocarbon radical, for examplej an alkyl radical such as methyl, ethylor propyl, or an alkenyl radical such as allyl, or a function-. allyconverted carboxyl group, for example,' a; carbomethoxy, carbethoxy orcarbobenzyloxygroup. Furthermore, they may contain i the} 7-position afree phenolic hydroxyl group or' a, substituent convertible into a freephenolic hysl droxyl group. The latter substituent may be, for: example,a hydroxyl group etherified by methanol, ethanol, a phenol, a benzylalcohol or the,

like or a hydroxyl group esterified by an organic,

or inorganic acid, or 2. nitro or amino group or a halogen atom. It ispreferable to start from; sterically uniform 1-keto-2-methyl-7-a1koxy--;l,2,3,4,9,10,11,12 octahydrophenanthrene -2-car--, boxylic acid methylesters, and particularly from,v the 1 keto 2 methyl-7-methoxy-compounds.The racemic l keto octahydrophenanthrenes used as starting material canbe obtained, for; example, by fractional crystallization, chroma-,-tography or sublimation. The optically active compounds may be preparedfrom the racemates inthe usual way. The reaction of the1-ketooctahydrophenanthrenes in the present process may be carried outin the manner prescribed in, the aforesaid application.

Thus, in order to introduce a hydrocarbon, radical into the 1-position,for example, an, alkyl radical such as methyl, ethyl or propyl, an,

alkenyl radical such as allyl, an aralkyl radical,

such as benzyl, or an alkinyl radical such as ethinyl, the startingmaterial may be reacted in a first reaction with the correspondingorgano-- metal compound, for example, with an organofl magnesium halideor organo-zinc halide, an alkylor alkinyl-alkali compound or the like.The newly introduced tertiary hydroxyl group may then be eliminateddirectly or indirectly from the resulting tertiary alcohols, if desiredafter hydrogenating any multiple bonds present in a side chain, This canbe brought about, for example, with the formation of a carbon-to-carbondouble bond. Thus, for example, water may be split ofi'gdirectly 01'thehydr'oxyl group may first 'be'exchangedfor halogen or another esteror ether residue. A hydroxyl group converted in this manner may then beeliminated, for example, by thermal decompositionor by treatment with anagent capable of splitting on acid or alcohol. The splitting oft of thetertiary hydroxyl group, which results from the above mentioned reactionwith the "organ-inetal compound, may also be brought about by thefurtheraction of an excess of the organo-metal compound at a raisedtemperature; The elimination of the hydroxyl group or the halogen.:atommay, however, also be brought about by reduction, for example, by meansof hydrogenin the presence of a noble metal catalyst or by meansof'hydriodic acid in the presence of glacial acetic acid. The conversionof the functionally converted carboxyl group in the -2'-position' and/orof the substituent in the' 7position into a free cairboxyl or hydroxylgroup respectively, may be brought about, especiall'y'in the case ofesters or ethers, bymeans E of hydrolyzing agents. However, in the caseof b'enzyl ethers, there may be used, for example, reducing agents. Anamino group in the 'l-position may beconverted into a hydroxyl group bydiazotization and boilifig. When both of the said substituents in the2'- and '7-positionsare to be converted into a free carbonxylj andhydroxyl "group, respectively, this maybe brought about in stages and ineither order-of succession.

"In order to saturate non-aromatic multiple carbon to-carbon bonds,especially double or triple-bonds introducedby splitting off thetertiar'y hydroxyl group or by reaction-with'unsaturated organo-metalcompounds, hydrogenation may be brought about at any desired stage ofthe process after the reaction W'iththe organometal 'compound. Forthispurpose there may be usedf-for example, chemical methods such ascatalytic or electrolytic hydrog'ention or hyd-ro droxyl group, may alsobe hydrogenated'in two different stages of the process. In particular,the multiple bond introduced with the unsatura't'ed residue may first besaturated with hydro'gen, then the tertiary hydrox'yl group eliminatedwith the formation of a double bond, and the latter subsequentlyhydrogenated.

-When the resulting compounds contain free carb'oxyl groups they may beesterified, for example, directly, by means of diazo-methane ordiazo-ethane or indirectly by Way of the acid chloride or an alkali saltof "the carboxylic acid in question. Finally, free phenolic hydroxygroups may be esterified oretherified in known manner. In thisconnection there may be mentioned esters with organic acids, especiallyaliphatic or aromaticacids, for example, acetic acid, 'propionic acid,butyric acid, palmitic acid,

stearic'acid or benzoic acid; or with sulionic acids, polycarboxylicacids "or carbo'xy-sulfonic and'the oily reaction product which isprecip acids, and finally with inorganic acids such as sulfuric acid orphosphoric acid or carbonic acid or derivatives of these acids. Amongthe ethers there are to be mentioned more especially, for example, thealkyl ethers such as the methyl, ethyl or propyl ethers, and theglucosides.

The free carboxylic acids may be converted into the carboxylic acidsalts, for example, alkali metal salts, alkaline earth metal salts orammonium salts. When the ester or etherresidue in the 'T-positibncontains basic groups, the corresponding salts with inorganic acids, forexample also the betaine ester salts may be made. The aforesaid saltsfind application more especially in aqueous solution or for depotherapy.

The products of the invention may find application as medic'aments or asintermediate prod- 'uets for the manufacture of medicaments.

I The following examples illustrate the invention, the parts being byweight unless otherwise stated, and the relationship of parts by weightto parts by volume being the same as that of the gram to the cubiccentimeter:

Example 1 6.04 parts 'of the 7-methoxy-loxo-2-methyl-1,2,3,'4,9,10,1l,12- octahydr'ophenanthrene-2- carboxylic acid methylester melting at 132-134" C.

and having theifo'rmul'a C 0 OCH;

(obtained, for example, by the fractional crystal volume of ether. Thereaction mixture "isth'en boiled for hour in a reflux apparatus, cooledwith ice, and decomposed with ice and hydro-- chloric acid. Then benzeneet her mixture, after being washed with water and dried leaves be' hindafter evaporation "a yellow colored thick on. The latter ban bedistilled without decomposition at 17 5-180''C. under a pressure of 0.02mm. The

colorless oil so obtained is 7-methoxy l-hydroxypheuanthrene-Z-carboXyIic acid methyl ester of the formula Itcrystallizes upon treatment with methanol;

After recrystallization from the same solvent it meltsatl'02-l03 C..

In order to eliminate water, 2.3 parts of the carbinol melting at'102-103" C. are dissolved in 20. parts by volume of pyridine, 4 partsby volume of phosphorus oxychloride are added, and the mixture is boiledfor /2 hour in areflux apparatus. After cooling, "the Whole is pouredinto ice,

itated is taken u in ether. The ethereal solution is washed withhydrochloric acid and water,

dried and evaporated. The residue is a pale brown oil, consisting ofcrude 7-methoxy-l-ethylidene- 2- methyl l,2,3,4,9,10,11,12octahydiophenanthrene-2-carboxylic acid methyl ester. In order tohydrolyze the carbomethoxy group the product is heated Withoutpurification in a mixture of 6 parts of potassium hydroxide and 20 partsby volume of alcohol of 95 per cent strength in an open vessel atl70-180 C. The resulting reaction mixture is diluted with water andextracted with ether. By mixing the aqueous alkaline solution soobtained with an excess of hydrochloric acid the unsaturated carboxylicacid is obtained. By fractional crystallization from acetone andmethanol there are obtained from the latter product two isomeric7-methoxyl-ethylidene-2-methyl- 1,2,3,4,9,10,11,12-octahydrophenanthrene-2-carbcxylic acids of the formula CH -CH.CH:

HaCO

in the form of rhombic crystals melting at 195- 197 C. and needlesmelting at 179-l81 C. re-

spectively. I

4.8 parts of a mixture of these two isomeric unsaturated carboxylicacids are, for the purpose of hydrogenation of the double bond resultingfrom the elimination of water, dissolved in 450 parts by volume ofmethanol, and hydrogenated at room temperature in the presence of 4.8parts of platinum oxide. When the absorption of hydrogen has ceased, thewhole is filtered to remove the catalyst and the methanol solution isevaporated. The crystalline residue is dissolved in acetone, thesolution is concentrated somewhat by evaporation, and allowed tocrystallize. The resulting needles consist of 7-methoxy-1- ethy1-2-methyl- 1,2,3,4,9,10,l1,12- octahydrophenanthrene-Z-carboxylic'acidmelting at 227-229 C. and having the formula COOH By evaporating themother liquors from which the above acid is obtained and repeatedrecrystallization of the residue from methanol, there is obtained theisomeric 7-methoxy-1- ethy1-2- methyl- 1,2,3,4,9,10,11,l2-octahydrophenanthrene-Z-carboxylic acid melting at 187- 188 C.

1 part of the methoxy-acid melting at 187-188 C. is heated with parts ofpyridine hydrochloride for 3 hours at 170-l80 C. in order to hydrolyzethe methoxy group. Hydrochloric acid and ether are added to the cooledmelt, and the mixture is agitated. The ethereal solution is then washedin turn with hydrochloric acid, a small quantity of a saturated solutionof sodium bicarbonate and water, dried, and evaporated, and afterrecrystallizing the residue from methanol, there is obtained7-hydroxy-.-1.-ethy1-2-.v

6 methyl 1,2,3,4,9,10,11,12 octahydrophenanthrene-Z-carboxylic acid inthe form of prismatic platelets melting at 181-182 C. and having theformula CH3 (3 O OH The methoxy-acid melting at 227-229 0., when treatedin an analogous manner yields the iso-i meric 7hydroxy-1-ethyl-2-methyl-1,23,43,10,--

l1,12-octahydrophenanthrene-2-carboxylic acid,

which after recrystallization from methanolmelts at 175-177 C. and is inthe form of glistenlng platelets. I

The hydrolysis of the methoxy group can also be carried out by heating 1part of the methoxy-' acid in a mixture of 5 parts of potassiumhydroxide and 12 parts by volume of methanol for 5 hours in a sealedtube at 200 C., and isolating the hydroxy-acid in the usual manner.

Example 2 10 parts of pulverized 7-methoxy-1-oxo-2- methyl1,2,3,4,9,l0,l1,12 octahydrophenanthrene-2-carboxylic acid methyl estermelting at 132-134 C. are introduced at 50 C., while stirring, into asolution of sodium acetylide, prepared from 5 parts of sodium, parts byvolume of liquid ammonia, a slight excess of acetylene and 100 parts byvolume of ether. After one hour the cooling mixture is removed,whereupon the ammonia slowly evaporates in the course of about 2 hours.An aqueous solution of ammonium chloride is added to the reactionmixture, and it is then extracted with ether. The ethereal solution iswashed with aqueous am-v monia solution and water, dried and evaporated.The residue is a snow white crystalline mass, which can be separated byfractional recrystallization from acetone and methanol into two 7-methoxy l hydroxy 1 ethinyl 2 methyl 1,2,3,4,9,10,11,12octahydrophenanthrene 2; carboxylic acid methyl esters of the formula"CECE HaCO melting at 158-159 C. and 117-120 C. respectively.

In order to convert the ethinyl group into an ethyl group, 7.8 parts ofthe higher melting ethinyl-carbinol, which is not entirely free from thelower melting isomer, are hydrogenated in 250 parts by volume ofmethanol in the presence of 0.8 part of platinum oxide. When thecalculated quantity of hydrogen has been absorbed the hydrogenationceases. The catalyst is then removed by filtration, and the methanolsolution is strongly concentrated. Upon cooling, more than 7 parts ofthe 7-methoxy-1-hydroxy-1- ethyl 2 methyl 1,2,3,4,9,l0,ll,12octahydrophenanthrene 2 carboxylic acid methyl ester melting at 102-l03C. described in Example 1, crystallizes.

Ezrample 3' By the procedure described in Example 2, 1.5

1 part the latter carbinol is then hydro genated in 50 parts by volumeofalcohol in the presence of 01 part of form 1,2,3,e,9,10,11,12octahydrophenanthrene2 cmboxylic acid methyl ester, which afterrecrystalli-- zation from methanol is obtained in the form of needlesmelting at 112.5-114" C. From the latter, the two isomeric7-methoXy-1-ethyl-2- methyl-1,2,33,29,10;1.12-octahydrophenanthrene-2-carboxylic acids which melt respectively at 17 9- 181 C. and 189-191C. may be obtained in the manner described in Example 1.

In an analogous manner the addition of acetylone and hydrogenation ofthe acetylenic'triple bond can be carried out with other 1-keto-octahy-'drophenanthrenes, for example, the raeemates'of 7methoxy-l-oxo-2-methyl-1,2,3, i,9,10,11,12 octahydrophenanthrene-2-carboxylic' acid methyl. ester melting at rel-102C. and 127-128 C.,I respectively. The resulting products are thenconverted into the corresponding octahys. hydrophenanthrena2-carboxylic.acids by the procedure described in Example 1. Thusyfor ex. ample, the7methoxy-1-ethyl-2-methyl-123,42; 9,10,11,12octahydrophenanthu'ene-2-carboxylic acid which melts at 213215 C. andwhich, upon splitting of the methoxy group, yields the correspondinghydroxy-acid which melts at 2-12-21? 0., may be obtained from the7-methoxy-l-oxof 2 methyl l,2,3,l,9,10,ll,12 octahydrophenan threne2-carboxylic acid methyl esterwhich has a'melting point of 127-428" C.Example 4 i 2.3 parts'of the 7- methoxyI-ethyl-Z-methyl-1,2,3,4,9,l0,11,12 octahydrophenanthrene-2-carboxylic acid melting at227229 C. described in Example 1 are suspended in 50 parts by volumetroleum ether the 'Z-rnethoxy-l-ethyl-2-methyle.

l,2,3,4,9,1il,l1,l2 octahydrophenanthrene-2-car+ boxylic acid chlorideofthe formula CH3 W000] moo a platinum catalyst to7-methoxy--l-hydroxy-l-ethyl-Z-methylmelts at -191 C. 2 parts of theacid chloride meltingatQO-Ql" C. are melted in an atmosphere of nitrogenwith 2 parts of l-menthol in an oil bath having a temperature of C. Atan oil bath temperature of about C. a vigorous evolution of hydrogenchloride occurs, and this ceases after 1 hour. The cooled melt isdissolved in a mixture of benzene and petroleum ether, and

chromatographed over 50 parts of aluminium By elutriating With petroleumether and evaporating the solvent the pure7-methoxy-lethyl-Z-methyl-1,2,3,4,9,10,11,12-octahydrophenanthrene-Z-carboxylic acid l-menthyl ester is obtained in the form of acolorless oil.

The above described acid chloride reacts in a similar manner, forexample, with alcohols, amino alcohols, hydroxya-cids or phenols withthe formation of the corresponding esters. The esterification of thecarboxyl group may be carried out by heatinga salt, for example, thesodium salt of the carboxylic acid, with an appropriate halogencompound.

Erample 5 1 part of the 7-hydroxy+1-ethyl-2-methyl- 1,2,3,4,9,l0,ll,l2octahydrophenanthrene-2-carboxylic acid melting at 18 1182 C. describedin Example 1 is mixed with asmall excess of an ethereal solution ofdiazo-methane. The resulting7-hydroxyl-ethyl-2-methyl-1,2,3,4,9,10,11,12-octahydrophenanthrene-2-carboxylic acid methyl ester obtained in theform of an oil' after evaporation of the solvent is dissolved, withoutpurification, in 30 parts by volume of a 2 N aqueous solution of sodiumhydroxide, and vigorously agitated after the addition of a small excessof dimethyl-sulfate. The precipitated oil is taken up in ether, theethereal solution is agitated with sodium hydroxide solution, and water,and after drying the solution, the solvent is evaporated.- Byrecrystallizing the residue from methanol, 7- methoxy-l-ethyl-2-methyl1,2,3,4,9,10,11,12-octahydrophenanthrene-2-carboxylic acid methyl estermelting at 120-121 C. and having the formula is obtained. The identicalcompound may be ob tained by direct esterification by means ofdiazomethane of the methoxy-acid, melting at 187-,

salt thereof, for example, an alkali salt, with the appropriate halide.

Example 6 1 part ofthe crude 7-hydroxy-1-ethy1-2-methyll,2,3,4,9,10,11,12 octahydrophenanthrene-Z- carboxylic acid methyl esterobtained bythe pro- 75 ceduredescribed in-Exa'mple. 5.is dissolvedinlfl:

into water, extracted with ether, and the ethereal solution is washed inturn with hydrochloric acid, sodium bicarbonate solution and water,dried, and distilled. By recrystallizing the residue from methanol. 7-acetoxy-l-.eth-.

yl-2-methyl 1,2,3,4,9,10,11,12-octahydrophenanthrene-2-carboxylic acidmethyl ester melting at 92-93 C. and having the formula CHaCOO Example 7A solution of 12 parts of 7-methoxy-1-oxo-2-methyl-1,2,3,4,9,10,11,1Z-octahydrophenanthrene- 2-carboxylic acidmethyl ester melting at 132- 134 C. in 150 parts by volume of benzene isrun at C., while thoroughly stirring, into a Grignard solution preparedfrom 1.4 parts of magnesium, 8.4 parts of methyl iodide and 150 parts byvolume of ether. The reaction mixture so obtained is then boiled for afurther hour in a reflux apparatus, then cooled, and decomposed with iceand dilute hydrochloric acid. After the addition of ether thebenzol-ether layer is Washed with water, dried and evaporated. Theresidue is a yellow oil which crystallizes in the form of needles uponthe addition of methanol. After recrystallization from methanol, the7-methoxy-1-hydroxy-1,2-dimethyl-1,2,3,4,9,10,11,12-octahydrophenanthrene-Z-carboxylicacid methyl ester or the formula COOCHI CH: CH

melts at 125-126 C. v

For the purpose of splitting off water, 2.5 parts of the latter carbinolmelting at 125-126" C. are boiled for A; hour in a mixture of 25 partsby volume of pyridine and 2.5 parts by volume of phosphorus oxychloride.After cooling, the whole is poured onto ice and hydrochloric acid,extracted with ether, and the ether evaporated after washing theethereal solution with water and drying it. The residue crystallizesimmediately after the addition of methanol. By further recrystallizationfrom methanol there is obtained therefrom pure 7-methoxy-1methylene-2-methy1-1,2,3,4;9,---

10,11,IZ-octahydrdphenanthrene 2 carboxylic} acid methyl esterv of theformula CH; COOOH;

in the form of platelets melting: at 1 15 116 c Alternatively, watermay, be split off by: boiling;

. 1 part of the carbinol in a mixture of 1 part of oxalic acid and'10par'ts of glacial acetic acid for several hours i'n'a reflux apparatus.

In order to hydrolyze the carbomethoxy roup, 2.5 parts of the crudeproductresulting from the splitting oil of water are dissolved in 10parts by volume of alcohol, and, after the addition of 7.5 parts ofpotassium hydroxide, heated at about C. in an open vessel until thepotassium salt precipitatesin solid form. The cooled meltis dissolved inwater, and small quantities of a neutral portion ar extracted fromthealkaline solution by means of ether. The aqueous alkaline layer isthen acidified-and the acid which is pre cipitated in crystalline formis fractionated by recrystallization from a mixture of acetone andmethanol. In this manner there is obtained mainly the7-methoxy-1-methylene-2-methyl- 1,2,3,4,9,10,11,12 octahydrophenanthrene2 carboxylic acid melting at -187 C. which crystallizes in the form ofprismatic plates. From the mother liquor the isomeric acid can beisolated in the form of rhombic crystals melting at 167-168" C.

8 parts of a mixture of the two unsaturated acids melting at 185-187 C.and 167168 C.. respectively are dissolved in 1000 parts by volume ofmethanol and hydrogenated in the presence of 8 parts of a platinumcatalyst at room temperature. After the quantity of hydrogen calculatedas one molecular equivalent has been absorbed the hydrogenation ceases.The catalyst is then removed by filtration, and the methanol solution isevaporated. By fractional crystallization from acetone and methanol,there are obtained from the residue two7-methoxy-1,2-dimethyl-1,2,3,4,9,10,11,1Z-octahydrophenanthrene-2-carboxylic acids of the formula COOH HsCO

1'. The racemic 7-methoxy-1-ethyl-2-methyl-1,2,13,49,110,11,I2-ectahydrophenanthrene 2 car boxyhc acid of theformula 2. The racemic 7-methqxy-1 ethyl-2-methyl- 1,2,3,4,9,10,11,12-octahydrophenainthrene- 2 camhqxylic acid of theformula having a melting pointof 189-191 C.

3. Amember selected from the group consisting 1 o,{ racemic7-methoxy-l-ethy1-2-methyl-l,2,3,4 ,e9.10.11,12,-octahydrophenanthrene-2 carboxylic acids which correspond tothe formula Y and. which have a melting point 01 187-188 C. 10 and189-191" C., respectively.

KARL MIESCHER. JULES HEER JEAN-RENE BILLETER. GEORG ANNER.

REFERENCES CITED The following referenes Eire of record in the file ofthis patent:

UNITED STATES PATENTS,

Name Date MewCcrrquodale et a1. J an; 26, 1937 OTHER REFERENCES Karrer:Organic Chemistry (Nordeman) pp. 91-92 (1938).

Anner et aL: Hev. Chim. Acta, vol. 30, pages 1422-1431 (1947).

Number

3. A MEMBER SELECTED FROM THE GROUP CONSISTING OF RACEMIC7-METHOXY-1-ETHYL-2-METHYL-1,2,3,49,10,11,12-OCTAHYDROPHENANTHRENE-2CARBOXYLIC ACIDS WHICH CORRESPOND TO THE FORMULA